Submissions for variant NM_003042.4(SLC6A1):c.131G>A (p.Arg44Gln)

dbSNP: rs794726859

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003595872	SCV001206235	pathogenic	Myoclonic-atonic epilepsy	2023-06-29	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC6A1 protein function. ClinVar contains an entry for this variant (Variation ID: 192368). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg44 amino acid residue in SLC6A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25865495, 27959697, 28191889). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This missense change has been observed in individual(s) with 34006619, clinical features of SLC6A1-related conditions, and/or myoclonic-atonic epilepsy (PMID: 25865495, 27959697, 28191889, 34006619). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 44 of the SLC6A1 protein (p.Arg44Gln).
CeGaT Center for Human Genetics Tuebingen	RCV001092965	SCV001249723	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001092965	SCV002567446	pathogenic	not provided	2022-08-22	criteria provided, single submitter	clinical testing	Reported in heterozygous state in one individual in an autism and intellectual disability cohort in published literature (Stessman et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29086036, 27959697, 25865495, 33004838, 35295842, 28191889)
OMIM	RCV003444212	SCV000224013	pathogenic	Myoclonic-astatic epilepsy	2015-05-07	no assertion criteria provided	literature only
Baylor Genetics	RCV003444212	SCV000328737	likely pathogenic	Myoclonic-astatic epilepsy	2016-05-01	no assertion criteria provided	clinical testing	Our laboratory reported two molecular diagnoses in ANKRD11 (NM_013275.5:c.3122C>A) and SLC6A1 (NM_003042.3:c.131G>A) in an individual with prematurity, delayed motor milestones, delayed speech, developmental regression, hearing loss, axial hypotonia, distal spasticity, seizure disorder, dysmorphic features, failure to thrive, feeding difficulties, and eye anomalies.
Rare Disease Center, Seoul National University Hospital	RCV003156080	SCV003845345	likely pathogenic	Autosomal dominant epilepsy	2023-03-23	no assertion criteria provided	research